N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide, is commonly known as Afatinib.
N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) is commonly known as Afatinib dimaleate.
Afatinib is investigational orally administered irreversible inhibitor of both the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. Afatinib is marketed as Afatinib dimaleate under the brand names Gilotrif in the United States and Giotrif in Europe.
Afatinib or its pharmaceutically acceptable salt was first generically disclosed in U.S. Pat. No. 6,251,912 and specifically disclosed in U.S. Pat. No. RE43,431.
U.S. Pat. No. 8,426,586 B2, WO2013052157 A1 and IPCOM000240150D described various crystalline forms of Afatinib dimaleate.
U.S. Pat. No. RE43,431 discloses process for the preparation of 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate (1:2). The said patent also discloses one pot process for the preparation of 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino). The disclosed process involves treatment of bromocrotonic acid with oxalyl chloride and N,N-dimethylformamide in methylene chloride to form crude bromocrotonic acid chloride, which is further treated with (S)—N-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine in tetrahydrofuran followed by treatment with N,N-dimethylamine to afford 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino) free base with less yield. Further it was purified by column chromatography, which is a laborious and time consuming process and also it is not suitable for commercial scale purpose.
Hence, there is a need in the art to develop an improved, economically viable and efficient, simple process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) with high yield and purity.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having same molecular formula and distinct physical properties like melting point, solubility profiles, thermal behaviors (e.g. measured by thermo gravimetric analysis—“TGA”, or differential scanning calorimetry—“DSC”), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry and differential scanning calorimetry. Solvent medium and mode of crystallization play very important role in obtaining a polymorphic form over the other.
Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms or polymorphs of compound of formula-1.